Abstract 15270: Macrophage ADAR1 Regulates Atherosclerosis Development Through Editing-Independent Degradation of PPAR-γ
Dunpeng Cai, Takashi Murashita, John Markley, Shiyou Chen, Ken Fujise, Douglas K Bowles- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Background: Macrophage activation and vascular inflammation play important roles in atherosclerosis. Non-editing functions of adenosine deaminase acting on RNA (ADAR1) in macrophage activation and atherosclerosis remain elusive.
Methods: Nonvascular ADAR1 in atherosclerosis progression was investigated via aortic transplantation and bone marrow transplantation. ApoE-/- mice combined with macrophage-specific ADAR1 deficiency were used to determine macrophage-specific roles of ADAR1 in atherosclerosis. Human coronary atherosclerotic specimens were utilized to establish the relevance to human atherosclerosis. Moreover, a humanized atherosclerosis model was created to examine the influence of human macrophages in human arteries.
Results: ADAR1+/– attenuates atherosclerosis. Allograft transplantation of wild-type abdominal aorta into ADAR1+/– recipient mice promoted atherosclerosis. Likewise, bone marrow transplantation from wild-type mice to ADAR1+/– recipient mice negated the protective effects of ADAR1+/–, suggesting that nonvascular ADAR1 is instrumental for atherosclerosis progression. ADAR1 deficiency in hematopoietic cells lessened the prevalence and severity of atherosclerosis, and impeded macrophage infiltration, foam cell formation, and aortic wall inflammation. Mechanistically, ADAR1 deletion deterred classical macrophage activation and foam cell formation via downregulation of PPAR-γ, which was mediated by enhancing ubiquitination and further degradation of PPAR-γ. Importantly, ADAR1 was upregulated in macrophages in human atherosclerotic lesions. Transplantation of ADAR1-deficient human monocytes, rather than their wild-type counterparts, into hyperlipidemic immunodeficient mice suppressed the formation of atherosclerosis in transplanted arteries from patients undergoing coronary artery bypass grafting surgery due to coronary artery blockade by atherosclerotic plagues. Interestingly, ADAR1 suppression in macrophages noticeably augmented the anti-atherosclerotic effect of the PPAR-γ agonist rosiglitazone.
Conclusions: These results demonstrate that noncanonical ADAR1 plays an essential role in the regulation of macrophage activation and atherosclerosis development.